GPCRおよびGタンパク質における分子間および分子内通信のメカニズム
Francesco Raimondi1, Michele Seeber, Pier G De Benedetti
1Dulbecco Telethon Institute (DTI), and Department of Chemistry, University of Modena and Reggio Emilia, via Campi 183, 41100 Modena, Italy.
Journal of the American Chemical Society
|March 14, 2008
まとめ
計算実験により,血栓素A2受容体 (TXA2R) とそのGタンパク質 (Gq) の間の通信経路が明らかになりました. アゴニストがTXA2Rに結合すると,ロドプシン型受容体シグナル伝達に不可欠なGタンパク質の活性化が促進されます.
科学分野:
- 分子薬理学 分子薬理学
- 計算式生体物理学について
- シグナルトランスデュークション.
背景:
- グアニジンヌクレオチド交換因子 (GEF) は,Gタンパク質の活性を調節することにより,細胞シグナル伝達を媒介する.
- トロンボキサンA2受容体 (TXA2R) は,様々な生理学的プロセスに関与するGタンパク質結合受容体 (GPCR) である.
- 受容体-Gタンパク質の相互作用を理解することは,細胞通信の解読の鍵です.
研究 の 目的:
- TXA2Rと同種のGタンパク質 (Gq) の間のコミュニケーションメカニズムを計算的に調査する.
- 受容体-Gタンパク質複合体における分子内および分子間通信を媒介する経路を解明する.
- 信号伝送に関わる主要な構造モチーフを特定する.
主な方法:
- 相互作用をシミュレートするために計算実験が採用されました.
- 分析は,TXA2RとGDPboundのGqヘテロトリマーとの結合に焦点を当てました.
- E/DRYモチーフやGqalpha C-terminusのような重要な領域が調査されました.
主要な成果:
- 受容体-Gタンパク質インターフェース,アゴニスト結合部位,および核酸結合部位の間には,双方向の通信経路が存在する.
- アゴニスト結合は,E/DRYモチーフの近くに溶媒のアクセシビリティを高め,Gqalpha C-terminusの浸透を促進します.
- E/DRYモチーフのアルギニンは,コミュニケーションを媒介する上で重要な役割を果たしています.
結論:
- この研究は,TXA2R-Gqシグナル伝達の分子基礎についての洞察を提供します.
- Gqalphaのα5-ヘリックスC端との受容体接触は,構造変化と核酸放出に不可欠である.
- 発見は,GPCRsのより広いロドプシンファミリーに関連しています.
関連する概念動画
G-protein Coupled Receptors
G-protein coupled receptors are ligand binding receptors that indirectly affect changes in the cell. The actual receptor is a single polypeptide that transverses the cell membrane seven times creating intracellular and extracellular loops. The extracellular loops create a ligand specific pocket which binds to neurotransmitters or hormones. The intracellular loops holds onto the G-protein.
G-protein Coupled Receptors
G-protein coupled receptors are ligand binding receptors that indirectly affect changes in the cell. The actual receptor is a single polypeptide that transverses the cell membrane seven times creating intracellular and extracellular loops. The extracellular loops create a ligand specific pocket which binds to neurotransmitters or hormones. The intracellular loops holds onto the G-protein.
Transducer Mechanism: G Protein–Coupled Receptors
G Protein–Coupled Receptors (GPCRs) are membrane-bound receptors that transiently associate with heterotrimeric G proteins and induce an appropriate response to various stimuli. GPCRs regulate critical physiological pathways and are excellent drug targets for treating diseases such as diabetes, cancer, obesity, depression, or Alzheimer's. Nearly 35% of approved drugs implement their therapeutic effects by selectively interacting with specific GPCRs.
GPCRs are also called heptahelical, 7TM, or...
GPCRs are also called heptahelical, 7TM, or...
G Protein-coupled Receptors
G Protein-Coupled Receptors or GPCRs are membrane-bound receptors that transiently associate with heterotrimeric G proteins and induce an appropriate response to sensory stimuli such as light, odors, hormones, cytokines, or neurotransmitters.
GPCRs are also called heptahelical, 7TM, or serpentine receptors, and consist of seven (H1-H7) transmembrane alpha-helices that span the bilayer to form a cylindrical core. The transmembrane helices are connected by three extracellular loops and three...
GPCRs are also called heptahelical, 7TM, or serpentine receptors, and consist of seven (H1-H7) transmembrane alpha-helices that span the bilayer to form a cylindrical core. The transmembrane helices are connected by three extracellular loops and three...
G Protein-coupled Receptors
G Protein-Coupled Receptors or GPCRs are membrane-bound receptors that transiently associate with heterotrimeric G proteins and induce an appropriate response to sensory stimuli such as light, odors, hormones, cytokines, or neurotransmitters.
GPCRs are also called heptahelical, 7TM, or serpentine receptors, and consist of seven (H1-H7) transmembrane alpha-helices that span the bilayer to form a cylindrical core. The transmembrane helices are connected by three extracellular loops and three...
GPCRs are also called heptahelical, 7TM, or serpentine receptors, and consist of seven (H1-H7) transmembrane alpha-helices that span the bilayer to form a cylindrical core. The transmembrane helices are connected by three extracellular loops and three...
Activation and Inactivation of G Proteins
Heterotrimeric G proteins are guanine nucleotide-binding proteins. As the name suggests, heterotrimeric G proteins are composed of three subunits: alpha, beta, and gamma. They remain GDP-bound or GTP-bound inside the cells and switch between inactive/active states. The Gα subunit possesses the nucleotide-binding pocket that binds guanine nucleotides and switches between GDP or GTP-bound states. In contrast, the Gꞵ and Gγ subunits are always bound together with high affinity and are together...


